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28 Mesenteric Lymphangioma 273
infection, hemorrhage and possibly malignant transformation. Following resection,
ongoing imaging is performed to exclude recurrences or residual lesions. Percutaneous catheter drainage and sclerotherapy has been performed as an alternative to
surgery in some cases.
Suggested Reading
1. Chen J, Du L, Wang DR. Experience in the diagnosis and treatment of mesenteric
lymphangioma in adults: a case report and review of literature. World J Gastrointest Oncol.
2018;10(12):522–7.
2. Grasso DL, Pelizzo G, Zocconi E, Schleef J. Lymphangiomas of the head and neck in children.
Acta Otorhinolaryngol Ital. 2008;28(1):17–20.
3. Johnson PT, Horton KM, Fishman EK. Nonvascular Mesenteric disease: utility of multide-
tector CT with 3D volume rendering. RadioGraphics. 2009;29(3):721–40.
4. Suthiwartnarueput W, Kiatipunsodsai S, Kwankua A, Chaumrattanakul U. Lymphangioma of
the small bowel mesentery: a case report and review of the literature. World J Gastroenterol.
2012;18(43):6328–32.
5. Rebuffini E, Zuccarino L, Grecchi E, Carinci F, Merulla VE. Picibanil (OK-432) in the
treatment of head and neck lymphangiomas in children. Dent Res J (Isfahan). 2012;9(Suppl 2):
S192–6.
Radiation-Induced Mesenteric Injury
Eli D. Ehrenpreis and Charles Broy
Pathophysiology of Radiation-Induced Tissue Injury
It is reasonable to expect that some damage to mesenteric tissue occurs during the
course of radiation therapy for solid tumors of abdominal organs and during
radiation therapy for lymphoma. Radiation deposits energy by changing neutral
atoms to ions. Adjacent anatomic structures that are exposed to therapeutically
administered radiation become innocent bystanders to these effects. In a biologic
environment, this causes activated oxygen species as well as irreparable damage to
DNA. The subsequent host response includes rapid inflammati on around the area of
exposure. These insults can cause long-term injury and possibly cell death.
Unfortunately, ionizing radiation effects all cells within the area of exposure and not
just the area of desired treatment. Routine imaging and radiation therapy for cancer
most often uses both X-Rays (photons) and electrons. Other heavy particles (including protons and neutrons) are also used. Although the repair process is more
efficient in normal cells than malignant cells, acute and chronic injurious affects to
normal tissue may occur.
The primary site of radiation-induced cellular injury is damage to double
stranded DNA. These effects are most pronounced in cells that exhibit rapid proliferation and cellular regeneration. In the abdomen, the rapid turnover of epithelial
cells that form the inner lining and glands within the intestinal organs are most
sensitive to the damaging effects of radiation. Other cell types, including the
mesenchymal-derived cells contained within the mesentery, are more radiation
resistant. The mesentery is a continuous structure to which the abdominal digestive
29
E. D. Ehrenpreis (&)
Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6 South,
Park Ridge, IL 60068, USA
e-mail: e2bioconsultants@gmail.com
C. Broy
Department of Gastroenterology, Edward Hines Jr VA Hospital, Hines, IL, USA
e-mail: Charles.Broy@va.gov
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_29
275
276 E. D. Ehrenpreis and C. Broy
organs are directly attached. The mesentery then collectively connects the
abdominal organs to the posterior abdominal wall. Within the mesenteric structure
are vascular, lymphatic and biliary systems. The surfaces of the mesentery are lined
with mesothelial cells. The undersurface of the mesothelium of the mesentery is
made up of connective tissue and also contains some mesenchymal cells. The
components of connective tissue include fibrocytes, adipose cells, collagen fibers,
and elastin fibers. Lymphatic channels and capillaries coalesce into larger structures
within the mesentery. The mesentery also contains macrophages, lymphocytes and
polymorphonuclear neutrophils (PMNs). (See Chap. 3, General Anatomy of the
Mesentery and Chap. 7, Cellular Anatomy of the Mesentery). Most of these cell
types have a low rate of mitotic activity and are relatively resistant to radiation
damage.
Radiation exposure causes increased bacterial translocation, inhibition of blood
vessel hormones and alters mast cell function in the rat/mouse model. All irradiated
blood vessels show loss of smooth muscle, intimal fibrosis, accumulation of foam
cells and luminal narrowing. This causes vascular insufficiency that may lead to
ulcerations, injury-prone vessels and bleeding. Irradiation of connective tissue can
cause a loss of flexibility and increased stiffness.
The most important factors in the development of radiation injury to normal
tissue are total radiation dose, fraction size, duration and the volume of organs
irradiated. The use of combination chemotherapy and radiation therapy results in
improved response and survival for a variety of cancers and is a standard approach
in modern oncology. Chemotherapies are often specifically applied as radiosensitizing agents in patients receiving radiation therapy. Concomitant chemotherapy
also enhances the risk of radiation injury. Although data is most robust for
5-fluorouracil-based chemotherapy, other agents including oxaliplatin and irinotecan have been implicated in worsening radiation damage to the abdominal organs.
Others risk factors include vascular disease, inflammatory bowel disease, collagen
vascular diseases and previous injury to the mesentery (Table 29.1). The relative
effects of these risk factors on the development of radiation-induced injury to the
mesentery have not been studied.
Table 29.1 Risk factors for the development of radiation injury to normal abdominal tissues
Risk factors
Cell type Rapidly dividing cells (epithelial cells, glands)
Radiation Total radiation dose, fraction size, duration and the volume of irradiated
Chemotherapy 5-fluorouracil, oxaliplatin, irinotecan
Medical
diseases
organs
Vascular disease, inflammatory bowel disease, collagen vascular diseases
and previous injury to the mesentery
29 Radiation-Induced Mesenteric Injury 277
Radiation-Induced Intestinal Injury-Enteropathy and Colopathy
Radiation-induced injury to the small and large intestine occurs in acute and chronic
forms. Acute intestinal toxicity is a result of destruction and delayed regeneration of
the intestinal epithelium. These changes are characterized by dilation of intestinal
crypts and mild inflammation. Epithelial atrophy and mucosal ulceration are subsequently followed by cellular regeneration and restoration of normal mucosa.
Clinical presentation of acute radiation inju ry of the intestine includes diarrhea,
nausea, and abdominal pain. The mechanism of chronic radiation enteropathy and
colopathy is complex and involves vascular inflammation, mucosal atrophy,
intestinal wall fibrosis, telangiectasia formation and vascular sclerosis. This can
present with deep ulcerations, gastrointestinal bleeding, altered motility, obstructive
symptoms, fistula formation, constipation, diarrhea from small intestinal bacterial
overgrowth, nutrient deficiencies from small intestinal malabsorption and intestinal
perforation.
Measures to prevent abdominal organ damage from radiation therapy include
displacement of the intestine away from the field of radiation, antioxidants, free
radical scavengers, dietary supplementation with glutamine. Research into cytokine
manipulation and modulators of endothelial function is ongoing.
The degree of involvement of the mesentery in the pathophysiology and clinical
manifestations of acute and chronic radiation-induced intestinal injury has not been
explored to date.
Medical Literature on Radiation and the Mesentery
Basic Research
Early studies in mice demonstrated that radiation of mesenteric vascular structures
produces increased cellularity of the arterioles and vascular permeability within
3 months changes, with a gradual recovery within a year. Vascular fibrosis, and
occasional luminal occlusion occurred after 18 months. Venous and capillary stasis
were described using a rat model. Acute vascular changes occur following conventionally fractionated RT with mitotic cell death without apoptosis occurring in
endothelial cells. Larger fractional radiation doses may cause apoptotic endothelial
cell death. Rapid hydrolysis of water stimulated by radiation exposure, induces the
production of hydroxide, superoxide, and hydroxyl radicals. These, in turn have
been implicated in the development of endothelial vascular injury. A single study
showed that the production of free radicals in the mesenteric circulation occurred
following leukocyte activation and adherence. Using a macaque model, a recent
study demonstrated that mesenteric lymph nodes in radiated animals showed
reduced number of lymphoid cells immediately after radiation exposure. Subsequently, mesenteric lymph nodes also developed fibrotic changes, that were
278 E. D. Ehrenpreis and C. Broy
attributed to abnormal immunomodulatory cells and/or signaling molecules that
originated from portions of the intestine with radiation-induced injury.
Of interest, various studies have shown that mesenchymal stem cells can
attenuate the injurious effects of radiation on tissues of the lung, periosteum, heart
and brain.
A study using a rat model demonstrated that an immune-enhanced diet containing arginine, omega-3-fatty acids and RNA fragments reduced bacterial counts
in mesenteric lymph nodes after radiation exposur e.
Clinical Publications
There is a single published case of a desmoid tumor of the mesentery that developed nineteen years after abdominal radiation therapy for Hodgkins disease.
Mesenteric stranding was found to occur in a study of four patients with radiation
enteropathy that underwent magnetic resonance enterography. A single case of
inadvertent injection of Y90 microspheres throughout the mesentery that occurred
during a radioembolization (RE) procedure was reported. The patient was treated
with amofostine and survived the exposure.
Summary
There is a true paucity of information currently available on the overall effects of
abdominal radiation on mesenteric physiology and function. The relationship
between radiation-induced mesenteric injury and acute and chronic entropathy,
colopathy and proctopathy have yet to be explored.
Suggested Reading
1. Hall CR. Pathology of radiation effects on healthy tissues in the pelvis. In: Ehrenpreis ED,
Marsh R de M, Small W, editors. Radiation therapy for pelvic malignancy and its
consequences. N.Y.: Springer;2015.
2. Gunnlaugsson A, Kjellén E, Nilsson P, et al. Dose-volume relationships between enteritis and
irradiated bowel volumes during 5-fluorouracil and oxaliplatin based chemoradiotherapy in
locally advanced rectal cancer. Acta Oncol. 2007;46:937.
3. Sehdev A, Marsh R de W. Contribution of chemotherapy to the toxicity of pelvic irradiation.
In: Ehrenpreis ED, Marsh R de M, Small W, editors. Radiation therapy for pelvic malignancy
and its consequences. N.Y.: Springer;2015.
4. Song DY, Lawrie WT, Abrams RA, et al. Acute and late radiotherapy toxicity in patients with
inflammatory bowel disease. Int J Radiat Oncol Biol Phys. 2001;51:455.
5. Lin A, Abu-Isa E, Griffith KA, Ben-Josef E. Toxicity of radiotherapy in patients with collagen
vascular disease. Cancer. 2008;113:648.
6. Panés J, Granger DN. Neutrophils generate oxygen free radicals in rat mesenteric
microcirculation after abdominal irradiation. Gastroenterology. 1996;111(4):981–9.
29 Radiation-Induced Mesenteric Injury 279
7. Parakkal D, Ehrenpreis ED. Medical management of radiation effects on the intestines. In:
Ehrenpreis ED, Marsh R de M, Small W, editors. Radiation therapy for pelvic malignancy and
its consequences. N.Y.: Springer;2015.
8. Atasoy BM, Deniz M, Dane F, Özen Z, Turan P, Ercan F, Çerikçioğlu N, Aral C, AkgünZ,
Abacioğlu U, Berrak Yeğen Ç. Prophylactic feeding with immune-enhanced diet ameliorates
chemoradiation-induced gastrointestinal injury in rats. Int J Radiat Biol. 2010;86(10):867–79.
9. Sabet A, Ahmadzadehfar H, et al. Survival after accidental extrahepatic distribution of Y90
microspheres to the mesentery during a radioembolization procedure. Cardiovasc Intervent
Radiol. 2012;35(4):954–7.
10. Feldmeier JJ, Hampson NB. A systematic review of the literature reporting the application of
hyperbaric oxygen prevention and treatment of delayed radiation injuries: an evidence based
approach. Undersea Hyperb Med. 2002;29:4.
11. Wegner HE, Fleige B, Dieckmann KP. Mesenteric desmoid tumor 19 years after radiation
therapy for testicular seminoma. Urol Int. 1994;53(1):48–9.
Drug Induced Mesenteric and Retroperitoneal Diseases
Sarah Burroughs and Eli D. Ehrenpreis
Definition
Nonocclusive mesenteric ischemia occurs as a sudden form of hypoperfusion of the
intestine that is not due to an arterial or venous mechanical blockage. Nonocclusive
arterial hypoperfusion is most commonly due to primary splanchnic arterial vasoconstriction, with the majority of cases involving vasospasm of branches of the
superior mesenteric artery supplying the small intestine and proximal colon. Several
vasoconstricting medications and drugs of abuse have been associated with the
development of nonocclusive mesenteric ischemia (Table 30.1).
The pathophysiology of the various types of mesenteric ischemia, including
non-occlusive mesenteric ischemia are shown in Fig. 30.1.
30
Epidemiology
While nonocclusive mesenteric ischemia accounts for 5 to 15 percent of patients
with acute mesenteric ischemia overall, the incidence of drug-induced nonocclusive
mesenteric ischemia has not been determined. The occurrence of nonocclusive
mesenteric ischemia in hospitalized patients has declined due to the to the widespread use of invasive hemodynamic monitoring, early correction of hypotension,
removal of pharmacologic and drugs of abuse, and the use of systemic vasodilators
in cardiac failure. Nonetheless the mortality for nonocclusive mesenteric ischemia
remains high, in part due to the complexity of establishing its diagnosis.
S. Burroughs E. D. Ehrenpreis (&)
Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6 South, Park
Ridge, IL 60068, USA
e-mail: e2bioconsultants@gmail.com
© Springer Nature Switzerland AG 2021
E. D. Ehrenpreis et al. (eds.), The Mesenteric Organ in Health and Disease,
https://doi.org/10.1007/978-3-030-71963-0_30
281
282 S. Burroughs and E. D. Ehrenpreis
Table 30.1 Medications and drugs of abuse associated with nonocclusive mesenteric ischemia
Medications and drugs of abuse associated with
nonocclusive mesenteric ischemia
Digoxin
Alpha-adrenergic agonists
Cocaine
Methamphetamine
Fig. 30.1 Pathophysiology associated with mesenteric ischemia. a Arterial thrombosis, b arterial
embolus, c nonocclusive mesenteric ischemia, d Venous thrombosis. Nonocclusive mesenteric
ischemia as shown in option C occurs via vasoconstriction
Patients at Risk
Patients who are at risk of developing nonocclusive mesenteric ischemia include
those who are critically ill, such as those with cardiogenic shock or sepsis and
patients with a history of cardiovascular disease such as congestive heart failure,
coronary artery disease. Drug-induced causes of nonocclusive mesenteric ischemia
is associated with medications, or drugs of abuse that are known to produce
intestinal vasoconstriction, such as digoxin, alpha-adrenergic agonists, cocaine, or
methamphetamine.
30 Drug Induced Mesenteric and Retroperitoneal Diseases 283
Pathophysiology
The pathogenesis of nonocclusive mesenteric ischemia is related to the regulation of
cardiac and cerebral blood flow at the expense of the splanchnic and peripheral
circulation. The neurohormonal mediators, vasopressin and angiotensin, are often
putative agents in the occurrence of nonocclusive mesenteric ischemia. When
nonocclusive mesenteric ischemia is caused by medications or drugs of abuse, such
as cocaine and methamphetamine, the primary instigating factor is drug-induced
sympathomimetic mesenteric vasoconstriction, leading to a spectrum of secondary
effects ranging from mild intestinal injury to frank bowel infarction. A number of
mechanisms have been described in the development of mesenteric ischemia from
cocaine abuse. These include (1) direct action of cocaine on the endothelium
causing vasoconstriction, (2) increased norepinephrine and activation of noradrenergic receptors causing vasoconstriction, (3) accelerated atherosclerosis, and
(4) platelet aggregation leading to mesenteric thrombosis. Similar to cocaine and
methamphetamine, digoxin can also induce a vasoconstrictive effect on the
splanchnic circulation, thereby increasing risk of mesenteric ischemia.
Diagnosis, Physical Findings and Laboratory Findings
The diagnosis of nonocclusive mesenteric ischemia is based on clinical suspicion
comprised of patient risk factors and clinical signs and symptoms of mesenteric
ischemic injury. Both the severity and location of abdominal pain in the setting of
nonocclusive mesenteric ischemia are highly variable. Patients often report having a
rapid onset of severe abdominal pain out of proportion to their accompanying
physical examination. In about twenty five percent of patients with nonocclusive
ischemia, abdominal pain may be absent or may start with nonspecific symptoms
such as bloating, nausea, and vomiting. Progressive abdominal pain may then
occur. Initial abdominal examination may be normal or nonspecific. The presence
of peritoneal signs such as rebound tenderness and guarding occur when ischemia
develops and transmural bowel infarction ensues. Nonocclusive mesenteric ischemia is often concomitant with other disor ders and clinical presentation resulting in
the masking of its symptoms. Because of this, necrosis and perforation may develop
before a definitive diagnosis can be established, adding to the urgency of making a
prompt diagnosis.
Laboratory studies can be nonspecific. Elevated white cell count, elevated serum
lactate, metabolic acidosis, and elevated hematocrit have all been shown to occur in
acute mesenteric ischemia.
284 S. Burroughs and E. D. Ehrenpreis
Imaging
Plain abdominal radiographs have a limited role in diagnosing mesenteric ischemia
and these are normal in 25% of cases. However, findings suggestive of all forms of
mesenteric ischemia include the presence of an ileus, bowel wall thickening, or
pneumatosis intestinalis. Computerized tomographic (CT) imaging of the abdomen
may also be nonspecific, but abdominal CT can be used rule out other causes of
acute abdominal pain. Findings consistent with acute mesenteric ischemia on
abdominal CT include focal or segmental bowel wall thickening, bowel dilation, or
mesenteric stranding (Also see Chap. 26, Ischemic Enteropathy).
Definitive imaging of nonocclusive mesenteric ischemia relies upon the
demonstration of narrowing or spasm of mesenteric vasculature. This can be
demonstrated on CT angiog raphy or selective mesenteric arteriography as reduced
intramural vessel filling, reduction in mesenteric vessels, and irregularity of the
arterial branches of the mesenteric vasculature on vascular imaging.
Treatment
The goal of treatment of patients with nonocclusive mesenteric ischemia is to
restore intestinal blood flow. Removal of vasoconstrictive medications is a critical
aspect of this treatment. If necessary, other medical agents with limited inhibitory
effects on mesenteric perfusion may be indicated. These agents include dobutamine,
dopamine, and milrinone. Hemody namic support, treatment of additional underlying causes, and intra-arterial infusion of vasodilators including papverine, prostaglandins, and nitroglycerine are also used. For patients with signs of advanced
bowel ischemia, abdominal exploration and possible bowel resection are indicated.
For patients suspected of having intestinal perforation surgical intervention should
not be delayed.
Prognosis
When compared with other forms of mesenteric ischemia, nonocclusive mesenteric
ischemia has the lowest survival with a mortality rates ranging from 70 to 90%.
This high mortality has been attributed to the severity of comorbid conditions that
contribute to the reduction of mesenteric perfusion, as well delay in diagnosis.
Several case studies have focused on the prognosis of drug- induced nonocclusive
mesenteric ischemia. Drugs such as methamphetamine and cocaine are associated
with a high risk of significant microvascular compromise and mesenteric ischemia.
Despite having fewer comorbidities, patients presenting with cocaine related
mesenteric ischemia have a relatively poor prognosis. In one study , 5 of 19 (26%)